PROJECT SUMMARY/ABSTRACT Specific configurations of the gut microbiome have been associated with colorectal cancer (CRC), but how gut microbes, their metabolites, and their interactions with the immune system potentiate colorectal carcinogenesis remains poorly understood. Fusobacterium nucleatum, a Gram-negative anaerobic bacterium, is a normal constituent of the human oral microbiome; however, numerous studies now demonstrate that F. nucleatum (Fn) is enriched in human colorectal adenomas and CRC compared to healthy colonic tissues. While our group has been involved in several of these studies under the aegis of this award; exactly how Fn promotes colonic tumorigenesis has not been fully elucidated. Clarifying the mechanisms by which Fn shapes the colonic tumor microenvironment will provide important insight for embarking on a multipronged approach to use Fn as a diagnostic and therapeutic target in CRC prevention and treatment. Based on the findings from our first funding cycle for this competitive R01 renewal, we formulate the overarching hypothesis that Fn is an oncomicrobe that through its effects on the CRC tumoral microbiota, via its oncometabolites, and by its direct interactions with intratumoral immune cells contributes to CRC growth and progression. Leveraging our knowledge and expertise with Fn, meta'omics, and mouse models, we will address how Fn potentiates colorectal carcinogenesis in its role as an oncomicrobe, via its short-chain fatty acids (oncometabolites), and in its interactions within the tumor immune microenvironment (oncoimmunology).